DESCRIPTION (From the Applicant's Abstract): The overall goal of this project is to utilize transgenic (Tg) mice as models for human familial prion diseases, which are linked to point and insertional mutations in the gene encoding the prion protein (PrP) on chromosome 20. We have previously constructed lines of transgenic mice that express a PrP molecule with a nine-octapeptide insertional mutation (PG14) associated with a familial form of Creutzfeldt-Jakob disease in humans. These Tg(PG14) mice develop a progressive neurological disorder characterized by ataxia, apoptosis of cerebellar granule cells, punctate deposition of PrP, and astrocytic gliosis. In addition, beginning at birth the mice accumulate mutant PrP molecules in their brains that display the major biochemical hallmarks of PrPSc, the pathogenic isoform of PrP. Thus, Tg(PG14) mice recapitulate several of the essential clinical, neuropathological, and biochemical features of inherited human prion diseases. These mice offer a unique opportunity to study the molecular and cellular basis of familial prion diseases in an in vivo setting, and to establish a rational basis for the future development of more effective diagnostic and therapeutic modalities. The purpose of the present application is to carry out further studies of the PG14 mutation in transgenic mice, with a view toward understanding how mutant PrP molecules cause the pathology seen in familial prion diseases, and what role the PrPSc isoform plays in this process. We plan to: (1) create new lines of Tg in which expression of mutant PrP is controlled by neuron-specific and inducible promoters; (2) investigate whether degradation of mutant PrP by theubiquitin-proteasome plays a role in the neuropathology observed in Tg(PG14) mice; and (3) compare the molecular, pathogenic, and transmission properties of two forms of mutant PrP that differ significantly in their degree of protease resistance.